Oxidative modification of LDL is considered an important pathogenetic factor in atherosclerosis. Studies from several laboratories have revealed that the biological effects triggered by mmLDL can largely be attributed to phospholipid oxidation products (Leitinger, N. et al. (1999) PNAS 96, 12010-12015; Watson, A. D. et al. (1995) J. Clin. Invest. 95, 774-782; Leitinger, N. et al. (1997) Adv. Exp. Med. Biol. 433, 379-382; Loidl, A. et al. (2003) J. Biol. Chem. 278, 32921-32928). Their increased levels in atherosclerotic plaques (Watson, A. D. et al. (1997) J. Biol. Chem. 272, 13597-13607; Itabe, H. et al. (1994) J. Biol. Chem. 269, 15274-15279) and the elevated antibody titers against oxidized phospholipids in humans and mice with lesions (Horkko, S. et al. (1999) J. Clin. Invest. 103, 117-128; Palinski, W. et al. (1995) Arterioscler. Thromb. Vasc. Biol. 15, 1569-1576; Palinski, W. et al. (1996) J. Clin. Invest. 98, 800-814) attract attention to the pathological relevance of these molecules.
A rapidly growing interest has been focused on two major representatives in the series of homologous oxidized phospholipids, namely 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC). Their importance is stressed by the finding that they selectively activate processes in vascular wall cells that may contribute to the pathogenesis of atherosclerosis as well as other chronic inflammatory diseases. Both lipids were demonstrated to be 3- to 6-fold enriched in rabbit atherosclerotic lesions corresponding to approximately 62 and 116 ng/mg of aorta wet weight PGPC and POVPC, respectively (Subbanagounder, G. et al. (2000) Arterioscler. Thromb. Vasc. Biol. 20, 2248-2254).
In WO 01/75170 A a method of evaluating the risk for atherosclerosis is described, in which a biological sample comprising HDL is contacted with an oxidized phospholipid and the change in the amount of oxidized or non-oxidized phospholipid is measured, wherein the absence of change in the amount of oxidized phospholipid indicates a risk for atherosclerosis.
As mentioned above, oxidized phospholipids are involved in the pathogenesis of atherosclerosis. Oxidized phospholipids are further known to be hydrolytically cleaved by enzymes which are associated with lipoproteins and have antiatherogenetic activity, for example phospholipases or PAF acetylhydrolases.